This invention generally concerns apparatuses for the electrically assisted delivery of a therapeutic agent. Such apparatuses are referred to broadly herein as electrotransport devices.
More specifically, this invention relates to electrotransport drug delivery devices in which active species or drugs are directly or indirectly delivered through the skin of a patient by application of electromotive force. Yet more specifically; this invention relates to electrotransport devices having physically coupled, substantially rigid zones or regions wherein the means of coupling permits the zones or regions to be planar or non-planar and thereby to conform to complex, curved and non-planar surfaces.
Yet even more specifically, this invention relates to electrotransport devices, such as iontophoresis devices, having physically and electrically coupled rigid zones or regions which are maintained in intimate contact with a patient""s skin so as to deliver, transdermally, drug or therapeutic agent.
The present invention concerns apparatuses for transdermal delivery or transport of therapeutic agents, typically through iontophoresis. Herein the terms xe2x80x9celectrotransportxe2x80x9d, xe2x80x9ciontophoresisxe2x80x9d, and xe2x80x9ciontophoreticxe2x80x9d are used to refer to methods and apparatus for transdermal delivery into the body of therapeutic agent, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis, electroporation or a combination of these. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force across the therapeutic species reservoir-tissue interface.
As used herein, the terms xe2x80x9ciontophoresisxe2x80x9d and xe2x80x9ciontophoreticxe2x80x9d refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of charged or uncharged drug(s) or agent(s) by the combined processes of electromigration, electroosmosis, and electroporation.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900""s. Deutsch U.S. Pat. No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices, namely that the patient needed to be immobilized near a source of electric current. The Deutsch device was powered by a galvanic cell formed from the electrodes and the material containing the drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the drug. This device allowed the patient to move around during iontophoretic drug delivery and thus imposed substantially less interference with the patient""s daily activities.
In presently known iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient""s skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery; and usually to circuitry capable of controlling current passing through the device. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode. In some instances, the drug may be formulated such that in one formulation the drug ions are positively charged and in a second formulation the drug ions are negatively charged. In such situations, the positively charged drug ions may be delivered from the anode and/or the negatively charged drug ions may be delivered from the cathode. Hence, drug delivery may occur from one or both electrodes and may occur simultaneously as well as sequentially.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent or drug, preferably an ionized or ionizable species (or a precursor of such species) which is to be iontophoretically delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents.
Perhaps the most common use of iontophoresis today is in diagnosing cystic fibrosis by delivering pilocarpine transdermally. Iontophoretically delivered pilocarpine stimulates sweat production, the sweat is collected, and is analyzed for its chloride ion content. Chloride ion concentration in excess of certain limits suggests the possible presence of the disease.
Electrotransport devices generally contain an electronic circuit which controls the current output of the device. In more recent years, the size of electrotransport devices has been reduced to a point where the devices can be mounted and worn on the skin. In order to protect, adequately, the electronic circuitry in such skin-mounted devices and for a variety of other reasons, these devices have generally utilized a substantially rigid container or assembly. See for example Lattin et al. U.S. Pat. No. 4,406,658 (FIGS. 2 and 3) and Lattin et al. U.S. Pat. No. 4,457,748 (FIGS. 1, 3 and 4). While these rigid devices were acceptable in those applications (e.g., cystic fibrosis diagnosis) which required the patient to wear the device for only a short period of time, i.e., on the order of 30 minutes or less, these devices have been found to be somewhat uncomfortable in those applications where the patient must wear the device for periods longer than an hour. Particularly in applications where the patient must wear the device for an extended period of time (e.g., days, weeks or months) comfort is a significant issue.
In response to these difficulties, the advantages of developing a flexible electrotransport delivery device were recognized. For example, Ariura et al. U.S. Pat. No. 4,474,570, discloses one example of a flexible iontophoresis device. This device utilizes electrode assemblies comprised of a current distributing conductive layer, a drug, or electrolyte salt-containing gel layer and a thin backing layer, all laminated together. The Ariura device utilizes minimal electronic circuitry, specifically only a single button cell battery which is connected though a flexible lead wire to an electrode assembly. In order to make the device completely flexible, Ariura utilizes thin xe2x80x9csheetxe2x80x9d batteries which have a thickness of only about 0.5 to 2 mm. Because the Ariura et al device is completely flexible, it is able to conform to many irregular body surfaces and can be worn comfortably for longer periods of time. While flexible iontophoretic delivery devices, such as that disclosed by Ariura et al. represent a significant advantage over rigid devices, in terms of comfort for the wearer, they present other disadvantages. For example, the Ariura et al. device is very limited in terms of the electronic circuitry which may be utilized in the device and yet still retain its flexible characteristics. Furthermore, there are many iontophoretic drug delivery applications which the current requirements are too high for the single small battery disclosed in the Ariura et al device. If multiple batteries are placed in the Ariura et al device, the device becomes substantially nonflexible and thereby loses its comfort advantage.
In addition to batteries, electrotransport delivery devices may have other components which are themselves relatively rigid and inflexible (i.e., one or more electrical components) or which require a relatively rigid housing in order to adequately protect the component during shipping and handling of the device. For example, xe2x80x9cdryxe2x80x9d electrotransport delivery devices which are hydrated immediately before use sometimes carry on-board water pouches. In order to adequately safeguard against premature hydration caused by inadvertent rupture of the on-board water pouches, it may be necessary to provide structural rigidity to the device at least in the vicinity of the water pouches. Other device components, e.g., delicate electronics, may require at least portions of the electrotransport device to be relatively rigid to provide protection, electrical continuity or other function.
Unfortunately, devices having rigid regions generally do not conform well to the body site to which the device is attached, particularly when the means of attachment is a releasable contact adhesive. This can cause an electrotransport system to peel away from the body site, or to alternatively cause internal layers of the device itself to detach or delaminate and thereby fail. This invention allows an electrotransport drug delivery device having rigid regions to conform to the body su face (e.g., to skin) to which it is adhesively held with a reduced tendency to peel away.
U.S. Pat. No. 4,752,285 to Petelenz discloses a wrist-disposed iontophoresis device held in place by a bracelet comprising an iontophoresis apparatus including a remote electrode. The iontophoresis apparatus and electrode of Petelenz ""285 are connected by wires to a separate current source.
The present invention overcomes the problems encountered in the prior art and is not suggested or disclosed in the references alone or in combination.
Briefly, in one aspect, the present invention is an assembly or device for delivering an agent by electrotransport through a body surface. A device of this invention has at least two rigid regions which are adapted to be maintained in ion-transmitting relationship with the body surface at spaced apart locations, and which are held in their spaced apart locations preferably by means of biocompatible adhesive. Despite substantial rigidity, at least a drug delivery component of the assembly of this invention is maintained in intimate, drug-transmitting relation with the body surface. A device of this invention further includes a flexible connector means which physically connects the rigid regions but which permits the rigid regions to move with respect to each other during agent electrotransport without loss of intimate contact with the surface of the patient""s body. Specific embodiments of flexible connector means of this invention include hinges and flexible polymeric webs.
In a preferred practice of this invention, the flexible connector means both (1) physically connects or couples the rigid zones; to one another and (2) electronically connects a component in one of the rigid zones to a component in the other rigid zone. Generally, this means that a flexible electronic conductor comprises a part of the flexible connector means.
In a preferred practice, the rigid components or zones of the assembly of this invention are held in intimate, ion-transmitting relation to a portion of a patient""s body by means of a biocompatible adhesive.
In yet another preferred practice, a device of this invention has a plurality of rigid zones and a plurality of flexible connector means physically or physically and electronically coupling the rigid zones.
In a further preferred practice of this invention, the rigid regions are contoured to the body surface to which they are applied.
Preferably, the rigid regions have a flexural rigidity, EI, greater than about 1.5xc3x9710xe2x88x923 kg-m2/rad and the flexible connector means has a flexural rigidity of less than about 0.75xc3x9710xe2x88x923 kg-m2/rad. More preferably, the rigid regions have a flexural rigidity of greater than about 5.0xc3x9710xe2x88x923 kg-m2/rad and the flexible connector means has a flexural rigidity of less than about 0.45xc3x9710xe2x88x923 kg-m2/rad. Most preferably, the rigid regions have a flexural rigidity of greater than about 15xc3x9710xe2x88x923 kg-m2/rad and the flexible connector means has a flexural rigidity of less than about 0.15xc3x9710xe2x88x923 kg-m2/rad. In addition, the difference between the flexural rigidity of a rigid region and the flexural rigidity of the flexible connector means (xcex94EI) is preferably greater than about 0.3xc3x9710 xe2x88x923 kg-M2/rad, more preferably greater than about 1.5xc3x9710xe2x88x923 kg-m2/rad, and most preferably greater than about 5.0xc3x9710xe2x88x923 kg-m2/rad.
The flexural rigidity of a rigid zone and/or a flexible connector means is measured in accordance with the test method described in connection with FIG. 12, hereinafter.